Throughout and within this application various technical and patent literature are referenced either explicitly or by reference to an Arabic numeral. The bibliographic citations for the Arabic numeral citations is found after the experimental examples. The contents of these technical and patent citations are incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Sensorineural hearing loss affects millions of people worldwide. In the mammalian auditory system, hair cells (HCs), the sensory receptor cell to sound and acceleration, are terminally differentiated cells. Degeneration of these cells, due to overstimulation, ototoxic drugs and aging, is the most common cause of hearing loss affecting ˜10% of the worldwide population. Since HCs provide survival promoting stimuli (1) to spiral ganglia neurons (SGNs), a secondary effect of HC loss is the gradual degeneration and death of SGNs, leading to structural and electrical remodeling of the cochlear nucleus (CN).
In mammals, this impairment is irreversible due to the incapacity of the cochlea to replace lost HCs. Cell replacement therapy has become an attractive solution for hearing restoration. Recent reports have demonstrated that limited new HCs may be regenerated de novo(2) or via phenotypical trans-differentiation(3, 4) within the adult mammalian inner ear. Moreover, a small number of new SGNs can also be generated from the mature inner ear (5). However, the production of new HCs and SGNs is a rare event. Thus, considerable efforts have been made to identify a renewable cell source able to reconstruct damaged inner ears, with a special focus on various progenitor cells(2, 6-8), albeit limited success.
Thus, there is a need for an effective, reproducible and clinically applicable method to generate functional hair cells. This invention satisfies this need and provides related advantages as well.